The large quantity of water insoluble protein isolated from an adult human lens indicate that the interactions of lens proteins are of fundamental importance in maintaining these crystallins "solubilized" in an intact lens. The variable size distribution and charge characteristics of the crystallins povide the structural basis for these interaction Lens opacification due to either the aggregation and insolubilization of proteins or the "lake" formation and density fluctuation effected by environmental factors involves changes in these interactions and/or complex formation. Either covalent modification or membrane malfunction affecting conditions in the milieu or a combination of both can result in reversible "clustering" and/or irreversible cross-linking of lens proteins and thereby opacification. The aggregation mechanism has been investigated by chemical modification using native alpha-crystallin as a model. Isolation and characterization of the variously sized populations resulting from reacting specific functional groups indicate that covalent modification and non-covalent interactions are effecting the aggregation of the native as well as subunits of alpha-crystallin. Data from circular dichroism studies and sedimentation in the analytical ultracentrifuge suggest that small or localized changes in amino acid side-chain chromophore(s) can cause the aggregation of lens proteins into different sized populations. Results from solvent and temperature perturbation studies indicate that the distribution and formation of lens crystallins in a medium of high density or temperature similar to that prevails in vivo are different from those observed in a dilute buffer. Thermodynamic analyses suggest the involvement of both reversible and irreversible equilibrium between crystallins and lenticular components. These initial studies indicate that soluble crystallins from normal lens interact and aggregate under simulated in vivo conditions. An investigation of the mechanism of crystallin complexing and interaction as a function of fiber development and aging will be undertaken. Information thus obtained will be valuable in elucidating the altered crystallin interactions responsible for the observed refractive inhomogeneity in senile human cataract.